P32: a sex- and gender-sensitive model for evidence-based precision medicine: from knowledge generation to implementation in the field of kidney transplantation
Authors: Ruth Sapir-Pichhadze, Sabine Oertelt-Prigione
Journal: Kidney International (2023)

Precision medicine emerged as a promising approach to identify suitable interventions for individual patients with a particular health concern and at various time points. Technology can enable the acquisition of increasing volumes of clinical and "omics" data at the individual and population levels and support advanced clinical decision making. However, to keep pace with evolving societal realities and developments, it is important to systematically include sex- and gender-specific considerations in the research process, from the acquisition of knowledge to implementation. Building on the foundations of evidence-based medicine and existing precision medicine frameworks, we propose a novel evidence-based precision medicine framework in the form of the P32 model, which considers individual sex-related (predictive [P1], preventive [P2], and personalized [P3] medicine) and gender-related (participatory [P4], psychosocial [P5], and percipient [P6] medicine) domains and their intersection with ethnicity, geography, and other demographic and social variables, in addition to population, community, and public dimensions (population-informed [P7], partnered with community [P8], and public-engaging [P9] medicine, respectively). Through its ability to contextualize and reflect on societal realities and developments, our model is expected to promote consideration of diversity, equity, and inclusion principles and, thus, enrich science, increase reproducibility of research, and ensure its social impact. Precision medicine emerged as a promising approach to identify suitable interventions for individual patients with a particular health concern and at various time points. Technology can enable the acquisition of increasing volumes of clinical and "omics" data at the individual and population levels and support advanced clinical decision making. However, to keep pace with evolving societal realities and developments, it is important to systematically include sex- and gender-specific considerations in the research process, from the acquisition of knowledge to implementation. Building on the foundations of evidence-based medicine and existing precision medicine frameworks, we propose a novel evidence-based precision medicine framework in the form of the P32 model, which considers individual sex-related (predictive [P1], preventive [P2], and personalized [P3] medicine) and gender-related (participatory [P4], psychosocial [P5], and percipient [P6] medicine) domains and their intersection with ethnicity, geography, and other demographic and social variables, in addition to population, community, and public dimensions (population-informed [P7], partnered with community [P8], and public-engaging [P9] medicine, respectively). Through its ability to contextualize and reflect on societal realities and developments, our model is expected to promote consideration of diversity, equity, and inclusion principles and, thus, enrich science, increase reproducibility of research, and ensure its social impact. Evidence-based medicine informs decision making in individual patients using the best evidence arising from the population studied. Harvesting the benefits of evidence-based medicine, however, is challenged by ineffective translation of knowledge into practice, on the one hand, and susceptibility to adverse effects in certain patient populations, on the other hand.1Adams S.M. Crisamore K.R. Empey P.E. Clinical pharmacogenomics: applications in nephrology.Clin J Am Soc Nephrol. 2018; 13: 1561-1571Crossref PubMed Scopus (15) Google Scholar,2Gross A.S. Harry A.C. Clifton C.S. et al.Clinical trial diversity: an opportunity for improved insight into the determinants of variability in drug response.Br J Clin Pharmacol. 2022; 88: 2700-2717Crossref PubMed Scopus (7) Google Scholar These observations led to a natural transition into the era of precision medicine. Precision medicine seeks to identify suitable interventions for individual patients with a particular health concern and at various time points.3Feldman A.M. Bench-to-bedside; clinical and translational research; personalized medicine; precision medicine-what's in a name?.Clin Transl Sci. 2015; 8: 171-173Crossref PubMed Scopus (15) Google Scholar Through reliance on molecular biomarkers, precision medicine helps design and implement preventative measures to mitigate the risks of experiencing undesirable outcomes. In recent years, there has been a growing interest in applying precision medicine tools in nephrology and kidney transplantation.4National Institute of Diabetes and Digestive and Kidney Diseases. Kidney Precision Medicine Project.https://www.niddk.nih.gov/research-funding/research-programs/kidney-precision-medicine-project-kpmpDate accessed: August 27, 2022Google Scholar, 5Sherwood K.R. Tran J. Günther O.P. et al.Genome Canada precision medicine strategy for structured national implementation of epitope matching in renal transplantation.Hum Immunol. 2022; 83: 264-269Crossref PubMed Scopus (9) Google Scholar, 6Can-SOLVE CKD NetworkPrecision medicine in diabetic kidney disease.https://cansolveckd.ca/research/theme-2/precision-medicineDate accessed: September 25, 2022Google Scholar, 7Oberbauer R. Meyer T.W. Precision medicine in transplantation and hemodialysis.Nephrol Dial Transplant. 2021; 36: 31-36Crossref PubMed Scopus (2) Google Scholar A call for precision medicine warrants the systematic inclusion of the concepts of "sex" and "gender."8Tannenbaum C. Ellis R.P. Eyssel F. et al.Sex and gender analysis improves science and engineering.Nature. 2019; 575: 137-146Crossref PubMed Scopus (279) Google Scholar, 9Laprise C. Cole K. Sridhar V.S. et al.Sex and gender considerations in transplant research: a scoping review.Transplantation. 2019; 103: e239-e247Crossref PubMed Scopus (21) Google Scholar, 10Melk A. Babitsch B. Borchert-Morlins B. et al.Equally interchangeable? how sex and gender affect transplantation.Transplantation. 2019; 103: 1094-1110Crossref PubMed Scopus (77) Google Scholar "Sex" is defined as the biological attributes of humans, including physical features, chromosomes, gene expression, hormones, and anatomy. A growing body of evidence suggests that disease distribution varies by sex in an age-adjusted manner. For example, the X chromosome carries a larger number of genes than the Y chromosome, and its incomplete inactivation may lead to imbalances in the availability of genetic material.11Carrel L. Willard H.F. X-inactivation profile reveals extensive variability in X-linked gene expression in females.Nature. 2005; 434: 400-404Crossref PubMed Scopus (1548) Google Scholar Gene expression also demonstrates sex bias, and mosaic loss of chromosome Y in blood cells is associated with increased all-cause mortality and cancer in aging men.12Fukami M. Miyado M. Mosaic loss of the Y chromosome and men's health.Reprod Med Biol. 2022; 21e12445Crossref PubMed Scopus (4) Google Scholar Hormonal variations throughout the lifespan can impact gene expression, modulate the immune function, and affect the likelihood of developing chronic diseases.13Mauvais-Jarvis F. Bairey Merz N. Barnes P.J. et al.Sex and gender: modifiers of health, disease, and medicine.Lancet. 2020; 396: 565-582Abstract Full Text Full Text PDF PubMed Scopus (734) Google Scholar In contrast to "sex," "gender" is defined as the individual's socially constructed roles, behaviors, expressions, and identities.14West C. Zimmerman D.H. Doing gender.Gender Soc. 1987; 1: 125-151Crossref Scopus (7217) Google Scholar In biomedical research, gender is frequently operationalized as the 4 dimensions of identity, roles, relations, and institutionalized gender—all of which are likely to affect a patient's tendency to acquire health conditions, seek health care, and participate in care.15Heise L. Greene M.E. Opper N. et al.Gender inequality and restrictive gender norms: framing the challenges to health.Lancet. 2019; 393: 2440-2454Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar Introduced over a decade ago, the P4 Medicine framework includes 4 domains (predictive [P1], preventive [P2], personalized [P3], and participatory [P4] medicine) and takes a systems approach to disease.16Hood L. Friend S.H. Predictive, personalized, preventive, participatory (P4) cancer medicine.Nat Rev Clin Oncol. 2011; 8: 184-187Crossref PubMed Scopus (556) Google Scholar P4 Medicine focused on the development of new technologies and the study of their socioeconomic impact, with patients acting as the major drivers in the realization of P4 Medicine through their participation in improving their health care. More recently, an updated P6 Medicine framework added psychocognitive and public domains. P6 Medicine aligned with the World Health Organization's definition of health as a state of complete physical, mental, and social well-being.17Bragazzi N.L. From P0 to P6 medicine, a model of highly participatory, narrative, interactive, and "augmented" medicine: some considerations on Salvatore Iaconesi's clinical story.Patient Prefer Adherence. 2013; 7: 353-359Crossref PubMed Scopus (57) Google Scholar Psychocognitive medicine (P5) focused on the role of psychological health in patients' quality of life, whereas P6 (i.e., the "public" domain) incorporated e-health, e-medicine, and telemedicine. In this review, we expand on the existing frameworks and present an innovative sex- and gender-sensitive P32 model for evidence-based precision medicine and illustrate how this revised framework can enhance the research process, as well as facilitate knowledge translation and implementation. The field of transplantation strives to allow each patient to enjoy his/her graft for his/her entire lifetime. To this end, the assessment of donor and recipient compatibility is a key consideration. Nowadays, organ allocation decisions rely on the demonstration of donor compatibility to the candidate based on blood group and human leukocyte antigens (HLAs). Transplant candidates will be allocated an organ so long as they do not demonstrate preformed antibodies against the donor's HLA (donor-specific antibodies). Patients who have a wide selection of antibodies against frequently observed HLA (or high panel-reactive antibodies) tend to wait longer for a compatible donor and are at an increased risk of dying on the waiting list.18Sapir-Pichhadze R. Tinckam K.J. Laupacis A. et al.Immune sensitization and mortality in wait-listed kidney transplant candidates.J Am Soc Nephrol. 2016; 27: 570-578Crossref PubMed Scopus (52) Google Scholar It is against this backdrop that we present the various components of our novel P32 framework. Avoidance of preformed donor-specific antibodies does not prevent new antibodies from forming post-transplant. The advent of gene sequencing saw growing efforts for evaluating how specific molecular HLA mismatches between donors and recipients19Norin A.J. Gebel H.M. Kamoun M. HLA antigens to epitopes: meeting the challenge.Hum Immunol. 2022; 83: 270-271Crossref PubMed Scopus (2) Google Scholar may induce immune injury and graft loss. The likelihood of observing immune injury in response to molecular incompatibility can vary as a function of sex-based differences in immune response, as described in the fields of autoimmunity, oncology, and infectious diseases.20Klein S.L. Flanagan K.L. Sex differences in immune responses.Nat Rev Immunol. 2016; 16: 626-638Crossref PubMed Scopus (2784) Google Scholar Biological sex also differentially affects aging of the immune system.21Hunt K. Wyke S. Gray C.M. et al.A gender-sensitised weight loss and healthy living programme for overweight and obese men delivered by Scottish Premier League football clubs (FFIT): a pragmatic randomised controlled trial.Lancet. 2014; 383: 1211-1221Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar For example, changing concentrations of sex hormones and age-related mosaic loss of chromosome Y in leukocytes can alter the transcription of immunoregulatory genes contributing to the immunologic sex differences observed throughout life and those apparent after puberty and before reproductive senescence. Prevention of immune injury secondary to molecular incompatibility can diminish risk of rejection and graft failure. When studying molecular determinants of immune sensitization, the significant polymorphisms observed across HLA genes warrant evaluation of diverse transplant candidates, including those with HLA types that are distinct from the donor pool. More importantly, in addition to ethnogeographic diversity, research into the epidemiology of immune sensitization must consider biological sex. This is because immune sensitization occurs in response to transfusions, transplantation, and childbearing, with the latter making women more likely to experience graft failure and less likely to access transplantation.22Bromberger B. Spragan D. Hashmi S. et al.Pregnancy-induced sensitization promotes sex disparity in living donor kidney transplantation.J Am Soc Nephrol. 2017; 28: 3025-3033Crossref PubMed Scopus (46) Google Scholar Human papilloma virus (HPV) vaccines serve as another illustrative example for the role patient's sex plays within the P2 domain. HPV vaccines have allowed significant protection against oncological strains of HPV, which cause cancers of the uterus, vulva, vagina, and oropharynx. In general, there is a known disparity in response to viral vaccines, impacting innate, humoral, and cell-mediated immune responses,23Klein S.L. Jedlicka A. Pekosz A. The Xs and Y of immune responses to viral vaccines.Lancet Infect Dis. 2010; 10: 338-349Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar resulting in greater vaccine efficacy in women versus men, and carrying important implications to preventive medicine20Klein S.L. Flanagan K.L. Sex differences in immune responses.Nat Rev Immunol. 2016; 16: 626-638Crossref PubMed Scopus (2784) Google Scholar for transplant patients specifically, and public health measures more generally. Genetic polymorphisms in sex chromosome and autosomal genes encoding immunologic proteins can differentially affect immunity and are apparent early in life. The significant polymorphism of the HLA gene complex makes perfect donor:recipient matching across HLA genes unlikely. To mitigate the risk of rejection, the field of transplantation has benefited from advances in immunosuppression. One of the major challenges, however, has been overcoming the adverse effects experienced by certain subgroups of patients (Figure 1). Sex influences the genome and epigenome, leading to sex-specific gene expression, protein levels, and function, thereby resulting in sex-specific therapeutic (efficacy) and sex-specific adverse (toxicity) drug effects.24Sharifi S. Caracciolo G. Pozzi D. et al.The role of sex as a biological variable in the efficacy and toxicity of therapeutic nanomedicine.Adv Drug Deliv Rev. 2021; 174: 337-347Crossref PubMed Scopus (13) Google Scholar More specifically, changes in drug absorption, distribution, metabolism, and elimination25Franconi F. Campesi I. Pharmacogenomics, pharmacokinetics and pharmacodynamics: interaction with biological differences between men and women.Br J Pharmacol. 2014; 171: 580-594Crossref PubMed Scopus (163) Google Scholar as well as sex-specific metabolic and transporter differences may affect the pharmacokinetics and pharmacodynamics (or drug target-related effects) of immunosuppressive agents. Given the narrow therapeutic range of certain immunosuppression agents and their associated complications (e.g., metabolic syndrome, cardiovascular disease, infections, and cancer), the field of transplantation relies on therapeutic drug monitoring. Intrapatient variability in trough blood levels of calcineurin inhibitors associates with rejection and graft failure. Although biological sex may differentially affect drug handling over time,26Klein S.L. Morgan R. The impact of sex and gender on immunotherapy outcomes.Biol Sex Differ. 2020; 11: 24Crossref PubMed Scopus (86) Google Scholar intrapatient variability has been primarily considered a marker of nonadherence.27van Gelder T. Within-patient variability in immunosuppressive drug exposure as a predictor for poor outcome after transplantation.Kidney Int. 2014; 85: 1267-1268Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Focusing solely on biological sex will, thus, not suffice, as patients' gender modulates adherence in adolescents and young adults after kidney transplantation.28Denhaerynck K. Steiger J. Bock A. et al.Prevalence and risk factors of non-adherence with immunosuppressive medication in kidney transplant patients.Am J Transplant. 2007; 7: 108-116Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar Hence, a broader perspective on the intersection between sex and gender is necessary. Gender-based risk factors of cardiovascular disease, like hypertension, hyperlipidemia, and diabetes, also intersect with sex-specific factors,29Yusuf S. Hawken S. Ounpuu S. et al.Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.Lancet. 2004; 364: 937-952Abstract Full Text Full Text PDF PubMed Scopus (8821) Google Scholar as well as age and genetic composition.30Lancia P. Jacqz-Aigrain E. Zhao W. Choosing the right dose of tacrolimus.Arch Dis Child. 2015; 100: 406-413Crossref PubMed Scopus (28) Google Scholar Accordingly, gender-specific interventional programs have been developed to target high-risk groups. Football Fans in Training, for example, is a 12-week program for overweight and sedentary men, built to address their needs and preferences while overcoming gendered barriers.31Gray C.M. Hunt K. Mutrie N. et al.Football Fans in Training: the development and optimization of an intervention delivered through professional sports clubs to help men lose weight, become more active and adopt healthier eating habits.BMC Public Health. 2013; 13: 232Crossref PubMed Scopus (117) Google Scholar WiseWoman and the PrimeTime Sister Circles, on the other hand, are programs specifically designed to address cardiovascular risks among women.32Vaid I. Wigington C. Borbely D. et al.WISEWOMAN: addressing the needs of women at high risk for cardiovascular disease.J Womens Health (Larchmt). 2011; 20: 977-982Crossref PubMed Scopus (17) Google Scholar,33Gaston M.H. Porter G.K. Thomas V.G. Prime Time Sister Circles: evaluating a gender-specific, culturally relevant health intervention to decrease major risk factors in mid-life African-American women.J Natl Med Assoc. 2007; 99: 428-438PubMed Google Scholar Kidney transplant recipients are known to have an increased cancer risk,34Webster A.C. Craig J.C. 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Chen H. et al.Comprehensive characterization of molecular differences in cancer between male and female patients.Cancer Cell. 2016; 29: 711-722Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar,37Missiaglia E. Jacobs B. D'Ario G. et al.Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features.Ann Oncol. 2014; 25: 1995-2001Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar including differences in the cytochrome P450 expression, distal-proximal resident microbiota, and metabolism impacting disease emergence and prognosis.38Cai Y. Rattray N.J.W. Zhang Q. et al.Sex differences in colon cancer metabolism reveal a novel subphenotype.Sci Rep. 2020; 10: 4905Crossref PubMed Scopus (27) Google Scholar In addition, colon cancer represents a compelling example for the interaction between sex and gender. For example, in the general population, competing substrates, such as oral contraceptives or gender-affirming hormones, emphasize the importance of gender-related considerations. Also, in the case of cancer screening, sex-specific differences in colon transit times might affect the diagnostic performance of fecal occult blood tests,39Brenner H. Haug U. Hundt S. Sex differences in performance of fecal occult blood testing.Am J Gastroenterol. 2010; 105: 2457-2464Crossref PubMed Scopus (107) Google Scholar whereas willingness to participate in screening has a gendered dimension. Finally, in long-term cancer survivors, gender-related consequences of disease affecting roles and social functioning impact men more than women.40Oertelt-Prigione S. de Rooij B.H. Mols F. et al.Sex-differences in symptoms and functioning in >5000 cancer survivors: results from the PROFILES registry.Eur J Cancer. 2021; 156: 24-34Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar To realize the benefits of precision medicine, we thus propose that gender is considered, in addition to sex, when seeking to individualize care. A successful patient-provider relationship should allow active participation of patients in care decisions. Gender may affect individual patient's tendency to actively participate in his/her care, be vulnerable to psychosocial stress, and benefit from care. In addition, patients and providers inject certain gendered expectations into the medical consultation process. Patients express gender-specific preferences when discussing sex-specific diseases. Also, patient experience and interpretation of quality of care and trust41Kruk M.E. Gage A.D. 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The impact of psychosocial stress often displays a gendered pattern, contributing to work-related stress attributed to an imbalance between effort and reward and unequal career opportunities,45Li J.A. Yang W.J. Cho S. Gender differences in job strain, effort-reward imbalance, and health functioning among Chinese physicians.Soc Sci Med. 2006; 62: 1066-1077Crossref PubMed Scopus (136) Google Scholar with women and gender nonconforming individuals most vulnerable to gendered discrimination.46Jenner S. Djermester P. Prugl J. et al.Prevalence of sexual harassment in academic medicine.JAMA Intern Med. 2019; 179: 108-111Crossref PubMed Scopus (59) Google Scholar Moreover, potential mismatch between gender identity and sex assigned at birth could represent an intrinsic and continuous stressor.47Valentine S.E. Shipherd J.C. 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By combining rigorous science with individualized care, evidence-based precision medicine represents the ideal approach for the special health needs of gender diverse and Gay, Lesbian, Bisexual, Transgender, Queer, Intersex, and Asexual (LGBTQIA) individuals. Specifically, guideline-making bodies are encouraged to generate unequivocable recommendations to avoid the conflation of biological sex and gender identity and to ensure clear indications for all potential patients.50Tannenbaum C. Clow B. Haworth-Brockman M. et al.Sex and gender considerations in Canadian clinical practice guidelines: a systematic review.CMAJ Open. 2017; 5: E66-E73Crossref PubMed Scopus (44) Google Scholar,51Caughey A.B. Krist A.H. 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Securing community partnership and public engagement increases the likelihood of knowledge translation and implementation of precision medicine. Accordingly, the next section will introduce the remaining 3 domains of the novel P32 evidence-based precision medicine necessary to inform and, eventually, capture benefits for individual patients. Registry-based studies have been the primary source of evidence-based medicine in transplantation. Registries combining information from multiple centers have ensured greater generalizability of findings and enhanced power to conduct multilevel and multivariable analyses addressing important confounders.53Massie A.B. Kucirka L.M. Segev D.L. Big data in organ transplantation: registries and administrative claims.Am J Transplant. 2014; 14: 1723-1730Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar In recent years, large consortia integrating standardized and interoperable large-scale high-throughput population-level demographic, clinical, and laboratory data as well as genomics, proteomics, and metabolomics have also come together. These interdisciplinary consortia are expected to transform the research process and generate novel evidence and breakthroughs, incorporating evidence-based precision medicine into clinical decision making. In addition to meta-analyses of traditional statistical methods,54Sawinski D. Trofe-Clark J. Leas B. et al.Calcineurin inhibitor minimization, conversion, withdrawal, and avoidance strategies in renal transplantation: a systematic review and meta-analysis.Am J Transplant. 2016; 16: 2117-2138Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar computational approaches, such as artificial intelligence tools,55Edwards A.S. Kaplan B. Jie T. A primer on machine learning.Transplantation. 2021; 105: 699-703Crossref PubMed Scopus (8) Google Scholar offer remarkable advancements when developing clinical prediction models. To pre